Intracellular combinatorial libraries offer great promise for generation of novel agonists and other molecules that perturb cellular physiology. However, there is a need for a general-purpose readout mechanism that is quantitative over a large dynamic range. For example, current selection methods for identifying agonists in solution generally depend on their interaction with receptors to change their physical state so that they activate an intracellular signal transduction domain that is linked to a pejorative reporter system. Thus, each reporter system requires a separate construct whose nature depends on specific information about the cell and molecular biology of the system in question. Such a selection scheme cannot lead to systems that can report on binding events, especially when the mechanism of signal transduction is not known.
There is a need in the art for more dynamic and universal methods for selecting ligands based on binding events. The present invention addresses this and other unmet needs in the art.